Project I: Oxytocin and Cocaine Dependence Co-Principal Investigators: Kathleen Brady and Aimee McRae-Clark; Co-Investigators: Jane Joseph, Megan Moran-Santa Maria Response to stress may be important in understanding sex/gender differences in drug dependence and may also be a target for developing both psychotherapeutic and pharmacotherapeutic interventions. Our previous SCOR work has suggested that the HPA axis in women may be more sensitive to the toxic effects of cocaine or early life trauma as compared to men; furthermore, cocaine-dependent women have a greater physiologic and subjective response to stress and the magnitude of this response may be related to the potential for relapse. As such, therapies focused on modulation of the stress response might be particularly important for women. Oxytocin is a hypothalamic neuropeptide that has been shown to mediate behavioral responding to stress as well as play a role in neuroadaptations that occur as a consequence of long-term drug use. Given these effects, oxytocin may have a therapeutic role in ameliorating the negative affect commonly observed prior to relapse in cocaine-dependent individuals. As estrogen appears to enhance oxytocin's effects, women may have an enhanced response to oxytocin. We propose an evaluation of the impact of oxytocin on the endocrine, physiological and subjective response to a validated laboratory stressor (the Trier Social Stress Task) in cocaine-dependent men (n=76) and women (n=76). In addition, fMRI will be used to evaluate the impact of oxytocin on functional brain activity in limbic and striatal nuclei during a cue- reactivity task and to assess gender differences in the neural response to oxytocin. The impact of estrogen and progesterone on stress and cue reactivity will also be measured. To our knowledge, this will be the first clinical investigation of oxytocin in cocaine-dependent individuals. Consistent with the overall theme of the MUSC SCOR, this project will directly explore the mechanistic underpinnings of the stress response in cocaine dependent men and women, and provide important data on a potential treatment approach. RELEVANCE (See instructions): Stress is likely involved in relapse to cocaine use. This project will investigate the role oxytocin may play in the stress response in cocaine-dependent men and women and examine how oxytocin may impact brain activity in individuals exposed to cocaine-related cues.